1. Field of the Invention
The present invention relates to a method for reversing or preventing extrapyramidal side effects consequent to neuroleptic treatment of psychiatric disorders by concurrently administering S-adenosyl-L-methionine (SAMe).
More specifically, the present invention relates to a method for reversing or preventing the onset of tolerance, and normalizing receptor binding, in patients undergoing prolonged neuroleptic treatment. Such patients often require increases in dosage to maintain therapeutic effects. Prolonged treatment also induces a proliferation of receptors, which is thought to contribute to extrapyramidal side effects often observed during treatment with neuroleptics. As a consequence of its effectiveness in reversing and/or preventing the onset of tolerance, and in normalizing receptor binding in patients undergoing treatment with neuroleptics, SAMe should find wide utility in human therapy.
2. Description of Related Art
Neuroleptic drug treatment is used in a wide variety of dementias. Chronic neuroleptic treatment with specific receptor antagonists, which occupy membrane receptors, normally up-regulates the specific receptors. Some antagonists also induce tolerance in which the dosage of drug must be increased to maintain its effect.
In contrast, supersensitivity occurs when there is an increase in bindable receptor number consequent to chronic receptor blockade with antagonist. An exaggerated response then occurs when this proliferation of binding sites is challenged with specific receptor agonist.
No drugs are presently available which are effective in preventing or reversing tolerance or normalizing receptor binding in patients undergoing prolonged neuroleptic treatment.
In many cases, the induction of tolerance and receptor proliferation supersensitivity are accompanied by undesirable extrapyramidal side effects such as tardive dyskinesia (TD). Extrapyramidal side effects are manifested as disorders in motor activities, affecting and impairing voluntary motion associated with postural, static, supporting, and locomotor mechanisms. Symptoms include tremors, muscular rigidity, dyskinesias such as TD, parkinsonism, or phenothiazene intoxication, etc. In the case of TD, specific manifestations include uncontrollable oral/facial movements such as grimacing and tongue protrusion. At present, such side effects are best prevented by using minimal dosages of neuroleptics for minimal time periods (Gerlach et al. (1988) Acta Psychiatr. Scand. 77:369-378). The neuroleptics in use today have antidopaminergic activity, which may contribute to the development of these side effects.
As discussed by Gerlach et al., the etiology of extrapyramidal side effects, specifically TD, is not definitely known at the present time. Certain factors seem to predispose toward the development of TD, which is considered to be the most serious side effect of neuroleptic treatment. The most important predisposing factors are: treatment with neuroleptic drugs, age, psychiatric diagnosis, prior extrapyramidal syndromes, and unknown individual factors. The prevention and treatment of TD are comprehensively discussed in this review.
In Europe, S-adenosyl-L-methionine has been used without side effects to treat patients for depression. The mechanism through which SAMe acts affects many different receptor systems, as well as other non-receptor related systems. A direct correlation has been found between membrane fluidity and receptor number (e.g., beta-adrenergic receptors, Hirata et al. (1979) Proc. Natl. Acad. Sci. USA 76:368-72). A decrease in membrane microviscosity yields a decreased number of available receptor-type binding sites, and an increase in microviscosity yields an increased number of available binding sites. S-adenosyl-L-methionine, an endogenous compound, has been shown to affect membrane fluidity (Cohen et al. (1988) J. Clin. Psychopharmacol. 8:43-47), perhaps by activating the methyltransferase complex for which it serves as the methyl donor for lipid methylation (Crews (1982) Psychopharmacol. Bull. 18:135-43; Hirata et al. (1980) Science 209:1082-90; Le Fur et al. (1983) Life Sci. 32:2321-28).
A large proportion of presently used neuroleptics are lipid-soluble compounds, and have an affinity for the lipid core of cell membranes, to which they segregate. The presence of a neuroleptic in cell membranes can change the physical/chemical properties of cell membranes, thus changing the way receptors and other biological systems respond to their particular signals.
While SAMe has been used therapeutically as an antidepressant and an anti-inflammatory agent, its use in the presently claimed manner for treating patients undergoing neuroleptic treatment has yet to be reported.